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  • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
  • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
• • C—CHEMISTRY; METALLURGY
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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  • C07C231/00—Preparation of carboxylic acid amides
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/82—Carbazoles; Hydrogenated carbazoles
  • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
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  • C07D213/68—One oxygen atom attached in position 4
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  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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  • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
  • C07H3/02—Monosaccharides

Definitions

• the present disclosure relates to a trifluoromethanesulfonylating agent composition capable of trifluoromethanesulfonylating a substrate containing a functional group such as a phenolic hydroxyl group, and a method for producing a trifluoromethanesulfonyloxy compound or a trifluoromethanesulfonyl compound using the same.
• the trifluoromethanesulfonylation of the phenolic hydroxyl group is an important reaction in the synthesis of the active pharmaceutical ingredients or pharmaceutical intermediates.
• Examples thereof include a method in which a substrate having a phenolic hydroxyl group is allowed to react with trifluoromethanesulfonic anhydride (Patent Literature 1, Non-Patent Literature 1, and Non-Patent Literature 2), a method in which a substrate having a phenolic hydroxyl group is allowed to react with trifluoromethanesulfonyl fluoride (Patent Literature 2), a method in which a substrate having a phenolic hydroxyl group is allowed to react with trifluoromethanesulfonyl chloride (Patent Literature 3), a method in which a substrate having a phenolic hydroxyl group is allowed to react with N-phenyl triflimide (Patent Literature 4), a method in which a substrate having a phenolic hydroxyl
• ketones, primary amines, or secondary amines have also been trifluoromethanesulfonylated.
• Non-Patent Literatures 4 and 5 disclose a method in which a substrate having a metalloenolate, a phenolic hydroxyl group, or a secondary amine is allowed to react with N-phenyl triflimide.
• Non-Patent Literature 6 discloses a method in which a metalloenolate is allowed to react with N-(2-pyridyl) triflimide, or a metalloenolate is allowed to react with N-5-chloro-2-pyridyl triflimide.
• Non-Patent Literatures 7 and 8 disclose a method in which a ketone is allowed to react with trifluoromethanesulfonic anhydride.
• An object of the present disclosure is to provide a trifluoromethanesulfonylating agent composition capable of trifluoromethanesulfonylating a substrate having a functional group such as a phenolic hydroxyl group.
• Another object of the present disclosure is to provide an efficiently and industrially feasible method for producing a trifluoromethanesulfonyloxy compound or a trifluoromethanesulfonyl compound.
• the present inventors have conducted extensive research. As a result, the inventors have found that the trifluoromethanesulfonylating agent composition of the present disclosure, which contains a specific trifluoromethanesulfonylating agent, can trifluoromethanesulfonylate a substrate having a functional group such as a phenolic hydroxyl group with preventing production of by-products.
• a trifluoromethanesulfonyloxy compound can be isolated from a reaction solution after a trifluoromethanesulfonylation reaction by merely carrying out a general post-treatment operation, and a trifluoromethanesulfonyloxy compound or a trifluoromethanesulfonyl compound can be efficiently obtained.
• a trifluoromethanesulfonylating agent composition capable of trifluoromethanesulfonylating a substrate having a functional group such as a phenolic hydroxyl group. Further, it is possible to provide an industrially feasible and efficient method for producing trifluoromethanesulfonyloxy compound or trifluoromethanesulfonyl compound using the above-described trifluoromethanesulfonylating agent composition.
• a trifluoromethanesulfonylating agent composition of the present disclosure (hereinafter also referred to as a composition of the present disclosure) contains a compound represented by the following Formula (1) or (11) as a trifluoromethanesulfonylating agent.
• R 1 is a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms,
• R 2 When there are a plurality of R 2 , R 2 may be the same or different, and when there are a plurality of R 3 , R 3 may be the same or different.
• R 5 is a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms, and Z - is an anion.
• R 1 represents a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms.
• linear alkyl group having 1 to 6 carbon atoms examples include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, and an n-hexyl group.
• Examples of the branched alkyl group having 3 to 6 carbon atoms include an isopropyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
• R 1 is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, because of ease of synthesis.
• R 2 represents a hydrogen atom, a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, a nitro group, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 6 to 14 carbon atoms.
• R 2 may be the same or different.
• linear aliphatic hydrocarbon group having 1 to 6 carbon atoms examples include a linear alkyl group having 1 to 6 carbon atoms, a linear alkenyl group having 2 to 6 carbon atoms, and a linear alkynyl group having 2 to 6 carbon atoms.
• linear alkyl group having 1 to 6 carbon atoms examples include the examples of the linear alkyl group having 1 to 6 carbon atoms which is described as R 1 .
• Examples of the branched aliphatic hydrocarbon group having 3 to 6 carbon atoms include a branched alkyl group having 3 to 6 carbon atoms, a branched alkenyl group having 3 to 6 carbon atoms, and a branched alkynyl group having 3 to 6 carbon atoms.
• Examples of the branched alkyl group having 3 to 6 carbon atoms include the examples of the branched alkyl group having 3 to 6 carbon atoms which is described as R 1 .
• Examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms include a phenyl group, a naphthyl group, and an anthryl group.
• Examples of the aromatic heterocyclic group having 6 to 14 carbon atoms include a pyrrole group, a pyrazine group, a pyrimidine group, and a pyridazine group.
• R 2 is preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, or a nitro group, and is more preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms.
• R 2 is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a nitro group, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
• X is a nitrogen atom or C(R 3 )
• Y is a nitrogen atom or C(R 4 ).
• R 3 represents a hydrogen atom, a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 6 to 14 carbon atoms. When there are a plurality of R 3 , R 3 may be the same or different.
• Examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, the branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, the aromatic hydrocarbon group having 6 to 14 carbon atoms, and the aromatic heterocyclic group having 6 to 14 carbon atoms include the examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, the branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, the aromatic hydrocarbon group having 6 to 14 carbon atoms, and the aromatic heterocyclic group having 6 to 14 carbon atoms, which are described as R 2 .
• R 3 is preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
• R 4 represents a hydrogen atom, a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 6 to 14 carbon atoms. When there are a plurality of R 4 , R 4 may be the same or different.
• Examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, the branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, the aromatic hydrocarbon group having 6 to 14 carbon atoms, and the aromatic heterocyclic group having 6 to 14 carbon atoms include the examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, the branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, the aromatic hydrocarbon group having 6 to 14 carbon atoms, and the aromatic heterocyclic group having 6 to 14 carbon atoms, which are described as R 2 .
• R 4 is preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
• X is preferably C(R 3 ), and Y is preferably a nitrogen atom.
• n is an integer of 1 to 3. n is preferably 1.
• R 2 and R 3 may bonded to form a ring.
• the ring formed by bonding of R 2 and R 3 is not particularly limited, and examples thereof include an aromatic hydrocarbon ring (for example, a naphthalene ring and an anthracene ring) having 6 to 14 carbon atoms or an aromatic heterocyclic ring having 6 to 14 carbon atoms.
• R 2 and R 4 may bonded to form a ring.
• the ring formed by bonding of R 2 and R 4 is not particularly limited, and examples thereof include an aromatic hydrocarbon ring (for example, a naphthalene ring and an anthracene ring) having 6 to 14 carbon atoms or an aromatic heterocyclic ring having 6 to 14 carbon atoms.
• X is C(R 3 ), and it is preferable that R 1 , R 2 , and R 3 each independently represent a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
• R 5 is a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms.
• Examples of the linear alkyl group having 1 to 6 carbon atoms and the branched alkyl group having 3 to 6 carbon atoms represented by R 5 include the examples of the linear alkyl group having 1 to 6 carbon atoms and the branched alkyl group having 3 to 6 carbon atoms, which are described as R 1 , and preferred examples are also the same.
• R 5 is preferably bonded to X or Y, and more preferably bonded to Y
• R 5 is bonded to the nitrogen atom in X to form a cationic moiety.
• R 5 is bonded to the nitrogen atom in Y to form a cationic moiety.
• Z - represents an anion
• Z - is preferably an anion of a strong acid or a superacid, more preferably a tetrafluoroborate anion, a hexafluorophosphate anion, a hexafluoroantimonate anion, a fluorosulfonate anion, a trifluoroacetate anion, a trifluoromethanesulfonate anion, a fluoromethanesulfonate anion, a methanesulfonate anion, a toluenesulfonate anion or a sulfonate anion, more preferably a trifluoromethanesulfonate anion, a fluoromethanesulfonate anion, a methanesulfonate anion, a toluenesulfonate anion or a sulfonate anion, and still more preferably a trifluoromethanesulfonate anion.
• a compound represented by Formula (11) is preferably a compound represented by the following Formula (11a).
• R 11 , R 12 , and R 15 are a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms,
• Examples of the linear alkyl group having 1 to 6 carbon atoms and the branched alkyl group having 3 to 6 carbon atoms as R 11 , R 12 , and R 15 include the examples of the linear alkyl group having 1 to 6 carbon atoms and the branched alkyl group having 3 to 6 carbon atoms, which are described as R 1 , R 2 , and R 5 in Formula (11).
• Xa is a nitrogen atom or C(R 13 ), and preferably C(R 13 ).
• Examples of the linear alkyl group having 1 to 6 carbon atoms and the branched alkyl group having 3 to 6 carbon atoms as R 13 include the examples of the linear alkyl group having 1 to 6 carbon atoms and the branched alkyl group having 3 to 6 carbon atoms, which are described as R 3 in Formula (11).
• Xa is C(R 13 ), and R 11 , R 12 , R 13 , and R 15 are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and particularly preferable that Xa is a hydrogen atom or a methyl group, from the viewpoint of ease of synthesis.
• Z - in Formula (11a) has the same meaning as Z - in Formula (11), and preferable examples thereof are also the same.
• trifluoromethanesulfonylating agent composition containing the compound represented by the above-mentioned Formula (1) or (11), it is possible to trifluoromethanesulfonylate a substrate having a phenolic hydroxyl group or the like, and one preferred aspect of the present disclosure is a trifluoromethanesulfonylating agent composition containing the compound represented by the above-mentioned Formula (1) and any base selected from the group consisting of an aliphatic organic base, an organic base having a heterocyclic group, and an inorganic base.
• a trifluoromethanesulfonylating agent composition containing the compound represented by Formula (1) and a specific base can selectively trifluoromethanesulfonylate the phenolic hydroxyl group with preventing production of by-products.
• the trifluoromethanesulfonyloxy compound can be isolated from a reaction solution after a trifluoromethanesulfonylation reaction by simply performing a general post-treatment operation, and a trifluoromethanesulfonyloxy compound can be obtained industrially and efficiently.
• the meaning that the trifluoromethanesulfonylating agent "selectively reacts" with a phenolic hydroxyl group is that the trifluoromethanesulfonylation reaction proceeds preferentially with the phenolic hydroxyl group.
• the first composition preferably contains the compound represented by Formula (1) in an amount of 80% or more, and more preferably 90% or more, based on a total mass of the first composition.
• the first trifluoromethanesulfonylating agent composition according to the present disclosure preferably contains a base.
• Examples of the base used in the first trifluoromethanesulfonylating agent composition include any base selected from the group consisting of an aliphatic organic base, an organic base having a heterocyclic group, and an inorganic base.
• the organic base is preferably a base selected from the group consisting of a secondary amine, a tertiary amine, an alkoxide, and an organic base having a heterocyclic group having a nitrogen atom and 4 or more carbon atoms.
• the aliphatic organic base is an organic base having an aliphatic hydrocarbon group and having no aromatic group.
• a secondary amine, a tertiary amine, or an alkoxide are preferred, and examples thereof include lithium methoxide, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, dipropylamine, diisobutylamine, trimethylamine, triethylamine, tri-n-propylamine, tributylamine, diisopropylethylamine, and N,N-diethylcyclohexylamine.
• the organic base having a heterocyclic group is preferably a compound having a heterocyclic group having 4 or more carbon atoms, and more preferably a compound having a heterocyclic group having a nitrogen atom and 4 or more carbon atoms.
• 1,8-diazabicyclo[5.4.0]undecene 1,5-diazabicyclo[4.3.0]nonene
• pyridine 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.
• the inorganic base is preferably a base selected from the group consisting of a sodium salt and a potassium salt, and examples thereof include sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
• hydrides of alkali metals are also preferred, such as sodium hydride and potassium hydride.
• the base is preferably any one selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium methoxide, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, tri-n-propylamine, tributylamine, diisopropylethylamine, N,N-diethylcyclohexylamine, 1,8-diazabicyclo[5.4.0]undecene, and 1,5-diazabicyclo[4.3.0]nonene.
• sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, or potassium tert-butoxide are preferred, and potassium carbonate, potassium bicarbonate, or potassium tert-butoxide are particularly preferred.
• sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, or potassium tert-butoxide are preferred, and potassium carbonate, potassium bicarbonate, or potassium tert-butoxide are particularly preferred.
• These bases can be used alone or in combination.
• the base when the base is an organic base, the organic base is preferably any one selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.
• An amount of the used base is not particularly limited, but is usually preferably from 0.01 mol to 20 mol, and more preferably from 0.05 mol to 5 mol, per 1 mol of a compound to be trifluoromethanesulfonylated, which will be described later.
• the first composition according to the present disclosure may further contain a solvent.
• the solvent is not particularly limited as long as the solvent dissolves the compound represented by Formula (1) above and the above base, and examples thereof include a reaction solvent for trifluoromethanesulfonylation to be described below.
• the first composition according to the present disclosure may or may not include the solvent.
• a method for producing a trifluoromethanesulfonyloxy compound using the first composition according to the present disclosure includes reacting the first trifluoromethanesulfonylating agent composition described above with a compound represented by the following Formula (2).
• the compound to be trifluoromethanesulfonylated with the first trifluoromethanesulfonylating agent composition (hereinafter also referred to as the compound to be trifluoromethanesulfonylated) is a hydroxylated aromatic compound represented by the following Formula (2).
• Ar represents an aromatic ring group or a substituted aromatic ring group.
• Ar represents an aromatic ring group or a substituted aromatic ring group.
• the aromatic ring group is not particularly limited, and may be a monocyclic or polycyclic ring.
• An aromatic ring group having 1 to 18 carbon atoms is preferred, and examples thereof include an aromatic hydrocarbon group such as a phenyl group, a naphthyl group, and an anthryl group, and an aromatic heterocyclic group containing a heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom, such as a pyrrolyl group (including a pyrrolyl group in which nitrogen is protected), a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyridazyl group, a triazyl group, a furyl group, a thienyl group, an indolyl group (including an indolyl group in which nitrogen is protected), an indazolyl group, a quinolyl group, a carbazolyl group, a pyrrolopyri
• Ar represents an aromatic ring group, and the aromatic ring group is preferably an aromatic heterocyclic group.
• the substituted aromatic ring group has any number and any combination of substituents on any carbon or nitrogen atom of the aromatic ring group.
• substituents include halogen atoms such as fluorine, chlorine, bromine, and iodine; lower alkyl groups such as a methyl group, an ethyl group, and a propyl group; lower unsaturated groups such as a vinyl group, an allyl group, and a propargyl group; lower haloalkyl groups such as a fluoromethyl group, a chloromethyl group, and a bromomethyl group; C(CF 3 ) 2 OH (including one in which a hydroxyl group is protected); lower alkoxy groups such as a methoxy group, an ethoxy group, and a propoxy group; lower haloalkoxy groups such as a fluoromethoxy group, chloromethoxy group, and a bromomethoxy group; lower acyloxy groups such as a formyloxy group, an
• Ar represents the substituted aromatic ring group
• a substituent of the substituted aromatic ring group is preferably a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a ⁇ -D-glucopyranoside group, an amino group, a lower alkylamino group, or a hydroxyl group.
• X' in the X'-Ar'-OH group represents a C(CH 3 ) 2 group, a C(CF 3 ) 2 group, an oxygen atom, a nitrogen atom (including a protected nitrogen atom), a sulfur atom, an SO group, or a SO 2 group
• Ar' represents a phenylene group or a substituted phenylene group.
• a substitution site of the phenylene group is 2-, 3- or 4-site relative to the hydroxyl group.
• a substituent of the substituted phenylene group is the same as the substituent of the substituted aromatic ring group.
• Specific examples of the hydroxylated aromatic compound represented by Formula (2) substituted with the X'-Ar'-OH group include the following compounds.
• the term "lower” means a linear or branched chain having 1 to 6 carbon atoms, or a cyclic group (in the case of having 3 or more carbon atoms).
• the aromatic ring group in the above "such substituents” can also be substituted with a halogen atom, a lower alkyl group, a lower unsaturated group, a lower haloalkyl group, a C(CF 3 ) 2 OH group (including a group in which a hydroxyl group is protected), a lower alkoxy group, a lower haloalkoxy group, a formyloxy group, a lower acyloxy group, a cyano group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a protected carboxyl group, a protected amino group, a hydroxyl group, a protected hydroxyl group, an X'-Ar'-OH group, and the like.
• protective groups for a pyrrolyl group, an indolyl group, a hydroxyl group, a carboxyl group, and an amino group are those described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons,Inc. , and the like.
• an aromatic ring group and a substituted aromatic ring group excluding a "hydroxyl group”, an “aromatic ring group”, and an “X'-Ar'-OH group” as the substituent are preferred, and an aromatic hydrocarbon group and a substituted aromatic hydrocarbon group (aromatic hydrocarbon group having a substituent) excluding a "hydroxyl group", an "aromatic ring group", and an "X'-Ar'-OH group” as the substituent are particularly preferred.
• fluorosulfonylation may occur a plurality of times depending on selected reaction conditions.
• a hydroxylated aromatic compound represented by Formula (2) has at least one selected from an alcoholic hydroxyl group and an amino group as a substituent. These substituents may be further substituted, for example, with the above-mentioned substituents of "such substituents".
• the hydroxylated aromatic compound represented by Formula (2) is preferably used in an amount of 0.7 to 1.2 mol per 1.0 mol of the trifluoromethanesulfonyl compound represented by Formula (1).
• the amount is more preferably from 0.8 to 1.0 mol.
• the above-described trifluoromethanesulfonylation reaction is preferably performed using a reaction solvent.
• reaction solvent for the trifluoromethanesulfonylation examples include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, amide solvents, nitrile solvents, and sulfoxide solvents.
• reaction solvents include ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 1,4-dioxane, and cyclopentyl methyl ether.
• ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 1,4-dioxane, and cyclopentyl methyl ether.
• Examples of the aliphatic hydrocarbon solvent include n-hexane, n-heptane, n-pentane, n-nonane, and n-decane.
• aromatic hydrocarbon solvents examples include toluene, xylene, mesitylene, and ethylbenzene.
• halogenated hydrocarbon solvents examples include methylene chloride, chloroform, and 1,2-dichloroethane.
• ester solvents examples include ethyl acetate, isopropyl acetate, n-butyl acetate, and ⁇ -butyrolactone.
• amide solvents examples include N,N-dimethylformamide, N, N-dimethy acetamide, N-methylpyrrolidone, and 1,3-dimethyl-2-imidazolidinone.
• nitrile solvents examples include acetonitrile, propionitrile, and benzonitrile.
• sulfoxide solvents examples include dimethyl sulfoxide.
• tetrahydrofuran, N,N-dimethylformamide, N, N-dimethy acetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile and dimethyl sulfoxide are preferred, and tetrahydrofuran, N,N-dimethylformamide, and acetonitrile are particularly preferred, because the compounds are easily available and have excellent solubility for the substrate and the trifluoromethanesulfonylating agent according to the present disclosure.
• reaction solvents can be used alone or in combination.
• An amount of the reaction solvent used in the trifluoromethanesulfonylation is not particularly limited, but it is sufficient to use 0.05 liters (L) or more per 1 mol of the compound to be trifluoromethanesulfonylated, usually from 0.1 to 20 L is preferred, and particularly from 0.1 to 10 L is more preferred.
• a reaction temperature for the trifluoromethanesulfonylation is not particularly limited, and the trifluoromethanesulfonylation is preferably carried out at a reaction temperature of 150°C or less, more preferably in a range of from -100 to 150°C, and still more preferably in a range of from -78 to 100°C.
• a reaction time for trifluoromethanesulfonylation is not particularly limited, but may be within a range of from 0.1 to 72 hours. Since the reaction time varies depending on raw materials and reaction conditions, it is preferable to follow progress of the reaction by an analytical method such as gas chromatography, liquid chromatography, or NMR and to end the reaction when the raw materials have almost disappeared.
• reaction solution containing the trifluoromethanesulfonyloxy compound after completion of the reaction with water, an acidic aqueous solution, or an alkali aqueous solution. That is, the reaction solution after the completion of the reaction may be diluted with an organic solvent, washed with water, an aqueous solution of a mineral acid (inorganic acid), or an aqueous solution of alkali metal salts, and a reaction mixture (organic phase) may be concentrated.
• organic solvent for the post-treatment examples include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, and ester solvents.
• organic solvents for the post-treatment include diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, cyclopentyl methyl ether, n-hexane, n-heptane, n-pentane, n-nonane, n-decane, toluene, xylene, mesitylene, ethylbenzene, methylene chloride, chloroform, 1,2-dichloroethane, ethyl acetate, and n-butyl acetate.
• reaction solvents can be used alone or in combination.
• An amount of the solvent for the post-treatment is not particularly limited, but it is sufficient to use 0.05 liters (L) or more per 1 mol of the compound to be trifluoromethanesulfonylated, usually from 0.1 to 20 L is preferred, and particularly from 0.1 to 10 L is more preferred.
• mineral acids for the post-treatment include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.
• hydrochloric acid and sulfuric acid are preferred, and hydrochloric acid is particularly preferred.
• alkali metal salts for the post-treatment include sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or potassium carbonate.
• the obtained trifluoromethanesulfonyloxy compound can be suitably and preferably used, for example, in a coupling reaction using transition metals.
• the trifluoromethanesulfonyloxy compound obtained by the first production method according to the present disclosure can be isolated from the reaction solution after the completion of the reaction by simply carrying out the simple post-treatment operation, the method can be carried out on an industrial scale, and as a result, it becomes possible to produce a coupling reaction product much more efficiently than by a method in the related art.
• Another preferred aspect of the present disclosure is a trifluoromethanesulfonylating agent composition containing the compound represented by the above Formula (11).
• the trifluoromethanesulfonylating agent composition containing the compound represented by Formula (11) (hereinafter also referred to as a second trifluoromethanesulfonylating agent composition, or simply as a second composition), not only a substrate having a phenolic hydroxyl group but also a wide range of substrates can be trifluoromethanesulfonylated, and trifluoromethanesulfonyl compounds derived from these substrates can be easily provided under industrially feasible conditions.
• the second composition according to the present disclosure includes a triflylimidazolium salt or a triflyltriazolium salt, which is a compound represented by Formula (11). Two or more of these may be used in combination.
• the second composition preferably contains the compound represented by Formula (11) in an amount of 80% or more, and more preferably 90% or more, based on a total mass of the second composition.
• the second composition according to the present disclosure may further contain a base.
• Examples of the base include a base which can be used in the trifluoromethanesulfonylation to be described below.
• the second composition according to the present disclosure may or may not include the base.
• An amount of the used base is not particularly limited, but is usually preferably from 0.01 to 20 mol, and more preferably from 0.05 to 5 mol, per 1 mol of a compound to be trifluoromethanesulfonylated, which will be described later.
• the second composition according to the present disclosure may further contain a solvent.
• the solvent is not particularly limited as long as the solvent dissolves the compound represented by Formula (11) and, in the case in which the second composition contains a base, the base, and examples thereof include a reaction solvent for the trifluoromethanesulfonylation to be described below.
• the second composition according to the present disclosure may or may not include the solvent.
• a method for producing a trifluoromethanesulfonyl compound using the second composition according to the present disclosure includes reacting the second trifluoromethanesulfonylating agent composition described above with the compound to be trifluoromethanesulfonylated.
• the compound to be trifluoromethanesulfonylated with the second trifluoromethanesulfonylating agent composition (hereinafter also referred to as the compound to be trifluoromethanesulfonylated) is preferably at least one substrate selected from the group consisting of a compound having a phenolic hydroxyl group, a compound having an alcoholic hydroxyl group, a ketone, a primary amine, and a secondary amine.
• An example of the compound having a phenolic hydroxyl group is a hydroxylated aromatic compound represented by the above Formula (2).
• Examples of the compound having an alcoholic hydroxyl group include an alkyl alcohol having 1 to 20 carbon atoms, methyl lactate, phenylethyl alcohol, and tetraacetyl- ⁇ -D-mannose.
• ketone examples include ethyl acetoacetate, acetylacetone, cyclohexanone, 1,3-cyclohexanedione, and ethyl 2-oxocyclohexanecarboxylate.
• Examples of the primary amine include alkylamines having 1 to 20 carbon atoms, aniline, 1-phenylethylamine, ⁇ -amino acids, and the like.
• Examples of the secondary amine include alkylamines having 1 to 20 carbon atoms, methylaniline, N-methylphenylethylamine, piperidine, and the like.
• the compound to be trifluoromethanesulfonylated not only those having one functional group in one molecule but also those having two or three functional groups in one molecule, can be trifluoromethanesulfonylated by the second trifluoromethanesulfonylating agent composition according to the present disclosure.
• fluorosulfonylation may occur a plurality of times depending on selected reaction conditions.
• the above-described trifluoromethanesulfonylation reaction is preferably performed using a reaction solvent.
• reaction solvent for the trifluoromethanesulfonylation examples include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, amide solvents, nitrile solvents, and sulfoxide solvents.
• reaction solvents include those described above as the reaction solvent in the first production method, and preferred examples are also the same.
• An amount of the reaction solvent used in the trifluoromethanesulfonylation is not particularly limited, but it is sufficient to use 0.05 liters (L) or more per 1 mol of the compound to be trifluoromethanesulfonylated, usually from 0.1 to 20 L is preferred, and particularly from 0.1 to 10 L is more preferred.
• the above-described trifluoromethanesulfonylation reaction is preferably performed using a base.
• Examples of the base include the bases described above as the base which can be contained in the first composition.
• the base is preferably triethylamine, sodium hydride, diisopropylethylamine, tributylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, or 3,5-lutidine, and more preferably triethylamine or sodium hydride.
• An amount of the used base is not particularly limited, but is usually preferably from 0.01 mol to 20 mol, and more preferably from 0.05 mol to 5 mol, per 1 mol of the compound to be trifluoromethanesulfonylated, which will be described later.
• a reaction temperature for the trifluoromethanesulfonylation is not particularly limited, and the trifluoromethanesulfonylation is preferably carried out at a reaction temperature of 150°C or less, more preferably in a range of from -100 to 150°C, and still more preferably in a range of from -78 to 100°C.
• a reaction time for the trifluoromethanesulfonylation is not particularly limited, but may be within a range of from 0.1 to 72 hours. Since the reaction time varies depending on raw materials and reaction conditions, it is preferable to follow progress of the reaction by an analytical method such as gas chromatography, liquid chromatography, or NMR and to end the reaction when the raw materials have almost disappeared.
• reaction solution containing the trifluoromethanesulfonyl compound after completion of the reaction with water, an acidic aqueous solution, or an alkali aqueous solution. That is, the reaction solution after the completion of the reaction may be diluted with an organic solvent, washed with water, an aqueous solution of a mineral acid (inorganic acid), or an aqueous solution of alkali metal salts, and a reaction mixture (organic phase) may be concentrated.
• organic solvent for the post-treatment examples include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, and ester solvents.
• organic solvent for the post-treatment examples include those described above as the organic solvent for the post-treatment in the first production method, and preferred examples are also the same. These organic solvents can be used alone or in combination.
• An amount of the solvent for the post-treatment is not particularly limited, but it is sufficient to use 0.05 liters (L) or more per 1 mol of the compound to be trifluoromethanesulfonylated, usually from 0.1 to 20 L is preferred, and particularly from 0.1 to 10 L is more preferred.
• mineral acid and the alkali metal salts for the post-treatment include those described above for the mineral acid and alkali metal salt for the post-treatment in the first production method, and preferred examples are also the same.
• the trifluoromethanesulfonyl compound obtained by the second production method according to the present disclosure can be isolated from the reaction solution after the completion of the reaction by simply carrying out the simple post-treatment operation, and therefore can be produced industrially and efficiently.
• a yield (%) is a value obtained by measuring a nuclear magnetic resonance spectrum 19 F-NMR.
• Synthesis Examples 1 to 3 and Examples 1 to 27 correspond to the first aspect using the trifluoromethanesulfonylating agent composition containing the compound represented by the above Formula (1) and the specific base. Further, Synthesis Examples 4 to 7 and Examples 28 to 35 correspond to the second aspect using the trifluoromethanesulfonylating agent composition containing the compound represented by the above Formula (11).
• reaction solution was filtered through celite (Celite, registered trademark: diatomaceous earth calcined with sodium carbonate, the same applies hereinafter) to remove insoluble matter, and acetonitrile was removed from a filtrate to obtain 9.7 g of 1-trifluoromethanesulfonylimidazole.
• reaction solution was filtered through celite to remove insoluble matter, and acetonitrile was removed from a filtrate to obtain 10.2 g of 1-trifluoromethanesulfonyl-2-methylimidazole.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, and a quantitative yield thereof was 100%.
• Example 1 a reaction in Example 1 will be shown.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, and a quantitative yield thereof was 100%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, and a quantitative yield thereof was 100%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, and a quantitative yield thereof was 100%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, and a quantitative yield thereof was 99%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, a quantitative yield thereof was 42%, and no side reaction was observed. Specifically, no signal derived from "methyl 2-trifluoromethanesulfonylamino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate" which may correspond to a by-product could be found.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-aminophenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 100%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 2-aminophenyl trifluoromethanesulfonate was found at -75 ppm, and a quantitative yield thereof was 48%. A signal derived from 1,1,1-trifluoro-N-(2-hydroxyphenyl)methanesulfonamide was found at -78 ppm, and a quantitative yield thereof was 17%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-(2-aminoethyl)phenyl trifluoromethanesulfonate was found at -75 ppm, and a quantitative yield thereof was 97%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-(2-hydroxyethyl)phenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 92%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-(2-hydroxyethyl)phenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 88%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 90%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 89%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from indol-5-yl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 87%. Signals derived from 1-(trifluoromethanesulfonyl)indol-5-yl trifluoromethanesulfonate were found at -74 ppm and -76 ppm, and a quantitative yield thereof was 5%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from indazole-6-yl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 74%. Signals derived from 1-(trifluoromethanesulfonyl)indazole-6-yl trifluoromethanesulfonate were found at -73 ppm and -75 ppm, and a quantitative yield thereof was 6%. A signal derived from 1-(trifluoromethanesulfonyl)indazol-6-ol was found at -75 ppm, and a quantitative yield thereof was 7%.
• Example 15 a reaction in Example 15 will be shown.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from carbazole-4-yl trifluoromethanesulfonate was found at -72 ppm, and a quantitative yield thereof was 98%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from pyridine-4-yl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 67%, but no side reactions were observed. Specifically, no signal derived from 1-(trifluoromethanesulfonyl)-4-[(trifluoromethanesulfonyl)oxy]pyridinium which may correspond to a by-product could be found.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from pyrrolo[2,3-b]pyridine-5-yl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 91%, but no side reaction was observed. Specifically, no signal derived from 1-(trifluoromethanesulfonyl)-pyrrolo[2,3-b]pyridine-5-yl trifluoromethanesulfonate which may correspond to a by-product could be observed.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl 2-hydroxy-4-(trifluoromethanesulfonyloxy)benzoate was found at -74 ppm, and a quantitative yield thereof was 76%. A signal derived from methyl 4-hydroxy-2-[(trifluoromethanesulfonyl)oxy]benzoate was found at -75 ppm, and a quantitative yield thereof was 5%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-trifluoromethanesulfonyloxyphenyl ⁇ -D-glucopyranoside was found at -74 ppm, and a quantitative yield thereof was 76%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-trifluoromethanesulfonyloxyphenyl ⁇ -D-glucopyranoside was found at -74 ppm, and a quantitative yield thereof was 75%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-aminophenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 80%, but no side reaction was observed. Specifically, no signal derived from "1,1,1-trifluoro-N-(2-hydroxyphenyl)methanesulfonamide" which may correspond to a by-product could be found.
• the reaction solution was adjusted to pH 1 by adding 5 mL of 1 mol/L hydrochloric acid, and then stirred at the room temperature for 5 minutes.
• the obtained solution was adjusted to pH 7 by adding 2.5 mL of a 1 mol/L sodium carbonate aqueous solution, and then transferred to a separatory funnel with 20 mL of tert-butyl methyl ether and 20 mL of clean water for layer separation.
• An obtained organic phase was further washed with 20 mL of clean water and dried with sodium sulfate.
• the obtained solution was filtered and concentrated under a reduced pressure to obtain 327 mg of methyl (2S)-2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate in an isolated yield of 100%.
• the reactor was sealed and stirred at 80°C for 6 hours to obtain a reaction solution.
• 20 mL of ethyl acetate was added, a mixture was washed with 20 mL of clean water, and then an organic phase was dried with sodium sulfate and concentrated under reduced pressure.
• the reaction solution was adjusted to pH 1 by adding 5 mL of 1 mol/L hydrochloric acid, and then stirred at the room temperature for 5 minutes.
• the obtained solution was adjusted to pH 7 by adding 2.5 mL of a 1 mol/L sodium carbonate aqueous solution, and then transferred to a separatory funnel with 20 mL of tert-butyl methyl ether and 20 mL of clean water for layer separation.
• An obtained organic phase was further washed with 20 mL of clean water and dried with sodium sulfate.
• the obtained solution was filtered and concentrated under reduced pressure to obtain 241 mg of 4-aminophenyl trifluoromethanesulfonate in an isolated yield of 100%.
• a 20 mL-sized Schlenk tube equipped with a stirring bar as a reactor was charged with 235 mg (4.04 mmol, 4.0 eq.) of potassium fluoride, 5 mL of tetrahydrofuran as a reaction solvent, and 241 mg (1.00 mmol, 1.0 eq.) of 4-aminophenyl trifluoromethanesulfonate as a substrate, and nitrogen bubbling was performed for 15 minutes.
• Example 24 The first and second reactions in Example 24 are shown below.
• the reaction solution was adjusted to pH 1 by adding 5 mL of 1 mol/L hydrochloric acid, and then stirred at the room temperature for 5 minutes.
• the obtained solution was adjusted to pH 7 by adding 2.5 mL of a 1 mol/L sodium carbonate aqueous solution, and then transferred to a separatory funnel with 20 mL of tert-butyl methyl ether and 20 mL of clean water for layer separation.
• An obtained organic phase was further washed with 20 mL of clean water and dried with sodium sulfate.
• the obtained solution was filtered and concentrated under reduced pressure to obtain 328 mg of methyl (2S)-2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate in an isolated yield of 100%.
• Example 25 The first and second reactions in Example 25 are shown below.
• the reaction solution was adjusted to pH 1 by adding 5 mL of 1 mol/L hydrochloric acid, and then stirred at the room temperature for 5 minutes.
• the obtained solution was adjusted to pH 7 by adding 2.5 mL of a 1 mol/L sodium carbonate aqueous solution, and then transferred to a separatory funnel with 20 mL of tert-butyl methyl ether and 20 mL of clean water for layer separation.
• An obtained organic phase was further washed with 20 mL of clean water and dried with sodium sulfate.
• the obtained solution was filtered and concentrated under reduced pressure to obtain 320 mg of methyl (2S)-2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate in an isolated yield of 98%.
• Example 26 The first and second reactions in Example 26 are shown below.
• the reaction solution was adjusted to pH 1 by adding 5 mL of 1 mol/L hydrochloric acid, and then stirred at the room temperature for 5 minutes.
• the obtained solution was adjusted to pH 7 by adding 2.5 mL of a 1 mol/L sodium carbonate aqueous solution, and then transferred to a separatory funnel with 20 mL of tert-butyl methyl ether and 20 mL of clean water for layer separation.
• An obtained organic phase was further washed with 20 mL of clean water and dried with sodium sulfate.
• the obtained solution was filtered and concentrated under reduced pressure to obtain 327 mg of methyl (2S)-2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate in an isolated yield of 99%.
• Example 27 The first and second reactions in Example 27 are shown below.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-(2-hydroxyethyl)phenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 40%. Further, signals derived from 4-[2-(trifluoromethanesulfonyloxy)ethyl]phenyl trifluoromethanesulfonate as a by-product were observed at -73 ppm and -75 ppm, and a quantitative yield thereof was 29%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from methyl (2S)-2-amino-3-(4-trifluoromethanesulfonyloxyphenyl)propanoate was found at -74 ppm, a signal derived from methyl (2S)-2-(4-nitroanilino)-3-[4-(trifluoromethanesulfonyloxy)phenyl]propanoate was found at -74 ppm, and quantitative yields thereof were 40% and 27%, respectively.
• the reactor was cooled with dry ice and charged with 10.6 g (69.4 mmol, 1.0 eq.) of trifluoromethanesulfonyl fluoride from a bomb.
• the reactor was returned to a room temperature and stirred for 18 hours to obtain a reaction solution.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from 4-(2-hydroxyethyl)phenyl trifluoromethanesulfonate was found at -74 ppm, and a quantitative yield thereof was 33%.
• two signals derived from by-products were observed at -74 ppm, and yields thereof were 15% and 11%, respectively.
• Examples according to the first aspect production of the by-products can be prevented and a trifluoromethanesulfonylated compound can be obtained in good yield.
• the phenolic hydroxyl group can be selectively trifluoromethanesulfonylated.
• the first reaction solution was filtered through celite (Celite, registered trademark: diatomaceous earth calcined with sodium carbonate, the same applies hereinafter) to remove sodium carbonate, and acetonitrile was removed from a filtrate to obtain 10.2 g of triflyl-2-methylimidazole (also referred to as "1-trifluoromethanesulfonyl-2-methylimidazole").
• the second reaction solution was concentrated, and 100 ml of tert-butyl methyl ether was added. Thereafter, a mixture was stirred at a room temperature for 22 hours. Precipitated crystals were filtered off under suction and obtained crystals were dried under reduced pressure to obtain 16.7 g of triflyl-2,3-dimethylimidazolium triflate in a yield of 72%.
• the first reaction solution was filtered through Celite, and acetonitrile was removed from an obtained filtrate to obtain 12.1 g of triflyl-1,2,4-triazole.
• the second reaction solution was concentrated, and 100 ml of tert-butyl methyl ether was added. Thereafter, a mixture was stirred at a room temperature for 22 hours. Precipitated crystals were filtered off under suction and obtained crystals were dried under reduced pressure to obtain 16.5 g of triflyl-4-methyl-1,2,4-triazolium triflate in a yield of 63%.
• the first reaction solution was filtered through Celite to remove sodium carbonate, and acetonitrile was removed from a filtrate to obtain 9.7 g of triflylimidazole (also referred to as "1-trifluoromethanesulfonylimidazole").
• the second reaction solution was concentrated, and 100 ml of tert-butyl methyl ether was added. Thereafter, a mixture was stirred at a room temperature for 15 hours. Precipitated crystals were filtered off under suction and obtained crystals were dried under reduced pressure to obtain 13.6 g of triflyl-3-methylimidazolium triflate in a yield of 50%.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from N-butyl triflimide was found at -73 ppm, a signal derived from N-butyltriflamide was found at -78 ppm, and quantitative yields thereof were 94% for N-butyltriflimide and 5% for N-butyltriflamide.
• Example 29 a reaction in Example 29 will be shown.
• Example 30 a reaction in Example 30 will be shown.
• Benzotrifluoride was added to the reaction solution as an internal standard, and when an analysis was performed by 19 F-NMR, a signal derived from N-phenyl triflimide was found at -71 ppm, and a quantitative yield thereof was 93%.
• a trifluoromethanesulfonylating agent composition of the present disclosure can be utilized as a trifluoromethanesulfonylating agent composition under industrially feasible conditions in synthesis of active pharmaceutical ingredients or pharmaceutical intermediates.

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